胰高血糖素样肽-1受体激动剂减轻小鼠体质量的作用机制研究

Mechanism of glucagon-like peptide 1 receptor agonist induced weight loss of mice

目的探讨胰高血糖素样多肽-1受体激动剂(GLP-1Ra)减轻小鼠体质量的作用机制。方法正常对照(N)组8只小鼠以普通饲料喂养,高脂饮食(HF)组32只以高脂饲料喂养,造模成功后的小鼠分为单纯HF组(HF)组、处死前寒冷刺激(CS)组和200、400μg/kg GLP-1 Ra干预[Lira(200)、Lira(400)]组,喂养8周。观察各组小鼠的体质量、血糖及三酰苷油(TG)的水平变化。HE染色观察小鼠不同部位白色脂肪(WAT)形态学改变;免疫组织荧光染色、Real-time PCR方法观察利拉鲁肽对棕色脂肪(BAT)特异因子UCP-1表达的影响;Western blot方法观察UCP-1表达的调节因子PPAR-γ共激活因子1α(PGC-1α)表达的影响。结果 Lira(200)组和Lira(400)组平均体质量低于HF组(P<0.05)。HF组较N组血糖和TG水平均升高,Lira(200)组和Lira(400)组血糖和TG水平较HF组降低(P<0.05)。Lira(200)组及Lira(400)组肾周与腹股沟皮下脂肪组织部分转变为含有微小脂滴的棕色样脂肪细胞,UCP-1蛋白和基因、PGC-1α蛋白表达水平较HF组均有不同程度的增加,Lira(400)组均强于Lira(200)组(P<0.05)。结论 GLP-1Ra能明显减轻小鼠体质量,其机制可能与增加UCP-1表达,促进白色脂肪发生棕色样变有关。

Objective To investigate the possible mechanisms of glucagon-like peptide 1 receptor agonists （GLP- 1Ra） induced weight loss. Methods High fat diet induced obese c57BL/6 mice were divided into normal control group （N, n=8）, high fat feeding group （HF, n=32） and GLP-1Ra group treated with GLP-1Ra （liraglutide 200 p,g/（kg, d） or 400 pg/（kg·d） for 8 weeks）. Changes of body weight, blood glucose and three aeyl glycosides （TG） levels were observed in three groups. HE staining was used to observe the morphological changes. Immunofluorescence staining and real-time PCR were used to measure the expression of UCP- 1. Furthermore, the expression of PGC- 1α in protein level was observed to explore the possible mechanism of GLP-1Ra induced browning in white fat （WAT）. Results After 8-week liraglutide （Lira） administration, the body weights were significantly reduced in obese mice （P 〈 0.05）. The levels of blood glucose and TG were significantly higher in HF group than those in N group, which reduced significantly in Lira （200 μg· kg-） and Lira （400 μg. kg-1） administra- tion groups （P 〈 0.05）. HE staining showed adipocytes in perirenal and inguinal subcutaneous adipose tissue partly acquired brown-like morphological characteristics. The expression levels of UCP-1 protein and mRNA and PGC-1α protein were ele- vated in adipse tissues, which increased more in Lira （400） than those in Lira （200, P 〈 0.05）. Conclusion GLP-1Ra can induce weight loss through white fat browning by activation of UCP- 1.